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1.
Eur J Nucl Med Mol Imaging ; 51(8): 2216-2228, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38532026

RESUMO

PURPOSE: Aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated mannosylated dextran derivative (Al[18F]F-NOTA-D10CM) is a new tracer for PET imaging. We report here on in vitro and in vivo validation of the tracer's ability to target the macrophage mannose receptor CD206. METHODS: First, the uptake of intravenously (i.v.) administered Al[18F]F-NOTA-D10CM was compared between wild-type (WT) and CD206-/- knockout (KO) mice. C57BL/6N mice were injected with complete Freund's adjuvant (CFA) in the left hind leg and the uptake of Al[18F]F-NOTA-D10CM after i.v. or intradermal (i.d.) injection was studied at 5 and 14 days after CFA induction of inflammation. Healthy C57BL/6N mice were studied as controls. Mice underwent PET/CT on consecutive days with [18F]FDG, i.v. Al[18F]F-NOTA-D10CM, and i.d. Al[18F]F-NOTA-D10CM. After the last imaging, Al[18F]F-NOTA-D10CM was i.v. injected for an ex vivo biodistribution study and autoradiography of inflamed tissues. Blood plasma samples were analyzed using high-performance liquid chromatography. To evaluate the specificity of Al[18F]F-NOTA-D10CM binding, an in vitro competitive displacement study was performed on inflamed tissue sections using autoradiography. CD206 expression was assessed by immunohistochemical staining. RESULTS: Compared with WT mice, the uptake of Al[18F]F-NOTA-D10CM was significantly lower in several CD206-/- KO mice tissues, including liver (SUV 8.21 ± 2.51 vs. 1.06 ± 0.16, P < 0.001) and bone marrow (SUV 1.63 ± 0.37 vs. 0.22 ± 0.05, P < 0.0001). The uptake of i.v. injected Al[18F]F-NOTA-D10CM was significantly higher in inflamed ankle joint (SUV 0.48 ± 0.13 vs. 0.18 ± 0.05, P < 0.0001) and inflamed foot pad skin (SUV 0.41 ± 0.10 vs. 0.04 ± 0.01, P < 0.0001) than in the corresponding tissues in healthy mice. The i.d.-injected Al[18F]F-NOTA-D10CM revealed differences between CFA-induced lymph node activation and lymph nodes in healthy mice. Ex vivo γ-counting, autoradiography, and immunohistochemistry supported the results, and a decrease of ~ 80% in the binding of Al[18F]F-NOTA-D10CM in the displacement study with excess NOTA-D10CM confirmed that tracer binding was specific. At 60 min after i.v. injection, an average 96.70% of plasma radioactivity was derived from intact Al[18F]F-NOTA-D10CM, indicating good in vivo stability. The uptake of Al[18F]F-NOTA-D10CM into inflamed tissues was positively associated with the area percentage of CD206-positive staining. CONCLUSION: The uptake of mannosylated dextran derivative Al[18F]F-NOTA-D10CM correlated with CD206 expression and the tracer appears promising for inflammation imaging.


Assuntos
Dextranos , Radioisótopos de Flúor , Lectinas Tipo C , Receptor de Manose , Lectinas de Ligação a Manose , Receptores de Superfície Celular , Animais , Camundongos , Lectinas Tipo C/metabolismo , Receptores de Superfície Celular/metabolismo , Lectinas de Ligação a Manose/metabolismo , Distribuição Tecidual , Dextranos/química , Manose/química , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Camundongos Endogâmicos C57BL , Macrófagos/metabolismo , Marcação por Isótopo , Compostos Heterocíclicos com 1 Anel
2.
Mol Pharm ; 21(8): 4147-4156, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39008899

RESUMO

Fatty acid binding protein 3 (FABP3) is expressed both in tumor cells and in the tumor vasculature, making it a potential target for medical imaging and therapy. In this study, we aimed to radiolabel a CooP peptide with a free amino and thiol group, and evaluate the radiolabeled product [18F]FNA-N-CooP for imaging FABP3 expression in breast cancer brain metastases by positron emission tomography. [18F]FNA-N-CooP was prepared by highly chemoselective N-acylation and characterized using different chemical approaches. We validated its binding to the target using in vitro tissue section autoradiography and performed stability tests in vitro and in vivo. [18F]FNA-N-CooP was successfully synthesized in 16.8% decay-corrected radiochemical yield with high radiochemical purity (98.5%). It exhibited heterogeneous binding on brain metastasis tissue sections from a patient with breast cancer, with foci of radioactivity binding corresponding to FABP3 positivity. Furthermore, the tracer binding was reduced by 55% in the presence of nonradioactive FNA-N-CooP a blocker, indicating specific tracer binding and that FABP3 is a viable target for [18F]FNA-N-CooP. Favorably, the tracer did not bind to necrotic tumor tissue. However, [18F]FNA-N-CooP displayed limited stability both in vitro in mouse plasma or human serum and in vivo in mouse, therefore further studies are needed to improve the stability [18F]FNA-N-CooP to be used for in vivo applications.


Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Proteína 3 Ligante de Ácido Graxo , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Animais , Humanos , Feminino , Camundongos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Proteína 3 Ligante de Ácido Graxo/metabolismo , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Radioisótopos de Flúor/química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/química , Linhagem Celular Tumoral , Peptídeos/química , Distribuição Tecidual , Compostos de Sulfidrila/química , Camundongos Nus
3.
J Nucl Cardiol ; 30(6): 2760-2772, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37758963

RESUMO

BACKGROUND: Vascular adhesion protein-1 (VAP-1) is an adhesion molecule and primary amine oxidase, and Gallium-68-labeled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetra-acetic acid conjugated sialic acid-binding immunoglobulin-like lectin 9 motif containing peptide ([68Ga]Ga-DOTA-Siglec-9) is a positron emission tomography (PET) tracer targeting VAP-1. We evaluated the feasibility of PET imaging with [68Ga]Ga-DOTA-Siglec-9 for the detection of myocardial lesions in rats with autoimmune myocarditis. METHODS: Rats (n = 9) were immunized twice with porcine cardiac myosin in complete Freund's adjuvant. Control rats (n = 6) were injected with Freund's adjuvant alone. On day 21, in vivo PET/computed tomography (CT) imaging with [68Ga]Ga-DOTA-Siglec-9 was performed, followed by ex vivo autoradiography, histology, and immunohistochemistry of tissue sections. In addition, myocardial samples from three patients with cardiac sarcoidosis were studied. RESULTS: [68Ga]Ga-DOTA-Siglec-9 PET/CT images of immunized rats showed higher uptake in myocardial lesions than in myocardium outside lesions (SUVmean, 0.5 ± 0.1 vs 0.3 ± 0.1; P = .003) or control rats (SUVmean, 0.2 ± 0.03; P < .0001), which was confirmed by ex vivo autoradiography of tissue sections. Immunohistochemistry showed VAP-1-positive staining in lesions of rats with myocarditis and in patients with cardiac sarcoidosis. CONCLUSION: VAP-1-targeted [68Ga]Ga-DOTA-Siglec-9 PET is a potential novel technique for the detection of myocardial lesions.


Assuntos
Miocardite , Sarcoidose , Humanos , Ratos , Animais , Suínos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioisótopos de Gálio/química , Miocardite/diagnóstico por imagem , Adjuvante de Freund , Tomografia Computadorizada por Raios X , Tomografia por Emissão de Pósitrons/métodos , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/química
4.
Am J Physiol Endocrinol Metab ; 320(5): E989-E998, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33843281

RESUMO

Cardiovascular effects of glucagon-like peptide-1 receptor (GLP-1R) agonist therapies are potentially mediated by anti-inflammatory effects on atherosclerosis. Our study demonstrates that 68Ga-NODAGA-exendin-4, a radioligand specifically targeting GLP-1R, detects GLP-1R expression in inflamed atherosclerotic lesions in nondiabetic and diabetic hypercholesterolemic mice. Immunofluorescence staining suggests that GLP-1R is primarily localized in M2 macrophages in lesions. This study describes a new potential tool that may have translational relevance for studies of pharmacological modification of GLP-1R signaling in atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Diabetes Mellitus Experimental/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Acetatos/farmacocinética , Animais , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Aterosclerose/complicações , Aterosclerose/diagnóstico , Aterosclerose/genética , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Experimental/genética , Exenatida/farmacocinética , Feminino , Radioisótopos de Gálio/farmacocinética , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Compostos Heterocíclicos com 1 Anel/farmacocinética , Hipercolesterolemia/complicações , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tomografia por Emissão de Pósitrons/métodos , Receptores de LDL/genética , Receptores de LDL/metabolismo
5.
J Neuroinflammation ; 18(1): 30, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33472663

RESUMO

BACKGROUND: Activated macrophages in the experimental model of multiple sclerosis (MS) express folate receptor-ß (FR-ß), representing a promising target for the treatment of MS. Here, we both evaluated the efficacy of a novel folate-aminopterin construct (EC2319) in a rat focal model of multiple sclerosis (MS) and investigated the utility of 68Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate (68Ga-FOL) for assessing inflammatory lesions. In addition, we investigated whether FR-ß is expressed in the brain of patients with MS. METHODS: Focal delayed-type hypersensitivity experimental autoimmune encephalomyelitis (fDTH-EAE) was induced in 40 Lewis rats; 20 healthy Lewis rats were used as controls. Rats were divided into six groups according to the duration of disease (control, acute, or chronic) and intervention (vehicle versus EC2319). 68Ga-FOL analyses, histology, and immunofluorescence of the brain were performed to evaluate the efficacy of subcutaneously administered EC2319 on lesion development. Immunofluorescence was used to assess FR-ß expression in postmortem brain samples from 5 patients with MS and 5 healthy controls. RESULTS: Immunofluorescence and histological analyses revealed significant reductions in FR-ß expression (P < 0.05) and lesion size (P < 0.01), as well as improved inducible nitric oxide synthase/mannose receptor C type 1 ratios (P < 0.01) in macrophages and microglia during the chronic but not acute phase of fDTH-EAE in EC2319-treated rats. The uptake of IV-injected 68Ga-FOL in the brain was low and did not differ between the groups, but the in vitro binding of 68Ga-FOL was significantly lower in EC2319-treated rats (P < 0.01). FR-ß positivity was observed in chronically active lesions and in normal-appearing white matter in MS brain samples. CONCLUSIONS: EC2319 was well tolerated and attenuated inflammation and lesion development in a rat model of a chronic progressive form of MS. Human MS patients have FR-ß-positive cells in chronically active plaques, which suggests that these results may have translational relevance.


Assuntos
Aminopterina/farmacologia , Encefalomielite Autoimune Experimental/patologia , Receptor 2 de Folato/metabolismo , Antagonistas do Ácido Fólico/farmacologia , Ácido Fólico/farmacologia , Animais , Humanos , Esclerose Múltipla/metabolismo , Ratos , Ratos Endogâmicos Lew
6.
Mol Biol Rep ; 48(6): 5347-5353, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34213709

RESUMO

Radiolabeled RGD peptides targeting expression of αvß3 integrin have been applied to in vivo imaging of angiogenesis. However, there is a need for more information on the quantitative relationships between RGD peptide uptake and the dynamics of angiogenesis. In this study, we sought to measure the binding of [68Ga]NODAGA-RGDyK to αvß3 integrin in a human cell-based three-dimensional (3D) in vitro model of angiogenesis, and to compare the level of binding with the amount of angiogenesis. Experiments were conducted using a human cell-based 3D model of angiogenesis consisting of co-culture of human adipose stem cells (hASCs) and of human umbilical vein endothelial cells (HUVECs). Angiogenesis was induced with four concentrations (25%, 50%, 75%, and 100%) of growth factor cocktail resulting in a gradual increase in the density of the tubule network. Cultures were incubated with [68Ga]NODAGA-RGDyK for 90 min at 37 °C, and binding of radioactivity was measured by gamma counting and digital autoradiography. The results revealed that tracer binding increased gradually with neovasculature density. In comparison with vessels induced with a growth factor concentration of 25%, the uptake of [68Ga]NODAGA-RGDyK was higher at concentrations of 75% and 100%, and correlated with the amount of neovasculature, as determined by visual evaluation of histological staining. Uptake of [68Ga]NODAGA-RGDyK closely reflected the amount of angiogenesis in an in vitro 3D model of angiogenesis. These results support further evaluation of RGD-based approaches for targeted imaging of angiogenesis.


Assuntos
Acetatos/farmacocinética , Compostos Heterocíclicos com 1 Anel/farmacocinética , Neovascularização Fisiológica/fisiologia , Oligopeptídeos/farmacocinética , Acetatos/farmacologia , Indutores da Angiogênese/farmacologia , Técnicas de Cultura de Células em Três Dimensões/métodos , Linhagem Celular Tumoral , Células Endoteliais , Radioisótopos de Gálio , Compostos Heterocíclicos com 1 Anel/farmacologia , Humanos , Integrina alfaVbeta3/metabolismo , Marcação por Isótopo/métodos , Modelos Biológicos , Neovascularização Fisiológica/efeitos dos fármacos , Oligopeptídeos/farmacologia , Distribuição Tecidual
7.
J Chem Phys ; 155(15): 154702, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34686040

RESUMO

Recent machine learning models for bandgap prediction that explicitly encode the structure information to the model feature set significantly improve the model accuracy compared to both traditional machine learning and non-graph-based deep learning methods. The ongoing rapid growth of open-access bandgap databases can benefit such model construction not only by expanding their domain of applicability but also by requiring constant updating of the model. Here, we build a new state-of-the-art multi-fidelity graph network model for bandgap prediction of crystalline compounds from a large bandgap database of experimental and density functional theory (DFT) computed bandgaps with over 806 600 entries (1500 experimental, 775 700 low-fidelity DFT, and 29 400 high-fidelity DFT). The model predicts bandgaps with a 0.23 eV mean absolute error in cross validation for high-fidelity data, and including the mixed data from all different fidelities improves the prediction of the high-fidelity data. The prediction error is smaller for high-symmetry crystals than for low symmetry crystals. Our data are published through a new cloud-based computing environment, called the "Foundry," which supports easy creation and revision of standardized data structures and will enable cloud accessible containerized models, allowing for continuous model development and data accumulation in the future.

8.
J Nucl Cardiol ; 27(6): 2386-2397, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-30547299

RESUMO

BACKGROUND: Activation of glucagon-like peptide-1 receptor (GLP-1R) signaling protects against cardiac dysfunction and remodeling after myocardial infarction (MI). The aim of the study was to evaluate 68Ga-NODAGA-exendin-4 positron emission tomography (PET) for assessment of GLP-1R expression after MI in rats. METHODS AND RESULTS: Rats were studied at 3 days, 1 and 12 weeks after permanent coronary ligation or a sham-operation. Rats were injected with 68Ga-NODAGA-exendin-4 and scanned with PET and contrast-enhanced computed tomography (CT) followed by digital autoradiography and histology of left ventricle tissue sections. 68Ga-NODAGA-exendin-4 PET/CT showed focally increased tracer uptake in the infarcted regions peaking at 3 days and continuing at 1 week after MI. Pre-treatment with an unlabeled exendin-4 peptide significantly reduced 68Ga-NODAGA-exendin-4 uptake. By autoradiography, 68Ga-NODAGA-exendin-4 uptake was 8.6-fold higher in the infarcted region and slightly increased also in the remote, non-infarcted myocardium at 1 week and 12 weeks post-MI compared with sham. Uptake of 68Ga-NODAGA-exendin-4 correlated with the amount of CD68-positive macrophages in the infarcted area and alpha-smooth muscle actin staining in the remote myocardium. CONCLUSIONS: 68Ga-NODAGA-exendin-4 PET detects up-regulation of cardiac GLP-1R expression during healing of MI in rats and may provide information on the activated repair mechanisms after ischemic myocardial injury.


Assuntos
Acetatos/química , Exenatida/química , Radioisótopos de Gálio/química , Receptor do Peptídeo Semelhante ao Glucagon 1/química , Compostos Heterocíclicos com 1 Anel/química , Infarto do Miocárdio/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia/métodos , Animais , Ecocardiografia , Perfilação da Expressão Gênica , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Cinética , Macrófagos/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
9.
Molecules ; 25(4)2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32079253

RESUMO

The enantiomers of aromatic 4-dibenzocyclooctynol (DIBO), used for radiolabeling and subsequent conjugation of biomolecules to form radioligands for positron emission tomography (PET), were separated by kinetic resolution using lipase A from Candida antarctica (CAL-A). In optimized conditions, (R)-DIBO [(R)-1, ee 95%] and its acetylated (S)-ester [(S)-2, ee 96%] were isolated. In silico docking results explained the ability of CAL-A to differentiate the enantiomers of DIBO and to accommodate various acyl donors. Anhydrous MgCl2 was used for binding water from the reaction medium and, thus, for obtaining higher conversion by preventing hydrolysis of the product (S)-2 into the starting material. Since the presence of hydrated MgCl26H2O also allowed high conversion or effect on enantioselectivity, Mg2+ ion was suspected to interact with the enzyme. Binding site predictions indicated at least two sites of interest; one in the lid domain at the bottom of the acyl binding pocket and another at the interface of the hydrolase and flap domains, just above the active site.


Assuntos
Candida/enzimologia , Lipase/metabolismo , Tomografia por Emissão de Pósitrons , Sítios de Ligação , Biocatálise , Domínio Catalítico , Dessecação , Esterificação , Íons , Cinética , Magnésio/farmacologia , Conformação Molecular , Simulação de Acoplamento Molecular , Estereoisomerismo
10.
J Neurochem ; 149(1): 41-53, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30565258

RESUMO

Muscimol, the major psychoactive ingredient in the mushroom Amanita muscaria, has been regarded as a universal non-selective GABA-site agonist. Deletion of the GABAA receptor (GABAA R) δ subunit in mice (δKO) leads to a drastic reduction in high-affinity muscimol binding in brain sections and to a lower behavioral sensitivity to muscimol than their wild type counterparts. Here, we use forebrain and cerebellar brain homogenates from WT and δKO mice to show that deletion of the δ subunit leads to a > 50% loss of high-affinity 5 nM [3 H]muscimol-binding sites despite the relatively low abundance of δ-containing GABAA Rs (δ-GABAA R) in the brain. By subtracting residual high-affinity binding in δKO mice and measuring the slow association and dissociation rates we show that native δ-GABAA Rs in WT mice exhibit high-affinity [3 H]muscimol-binding sites (KD ~1.6 nM on α4ßδ receptors in the forebrain and ~1 nM on α6ßδ receptors in the cerebellum at 22°C). Co-expression of the δ subunit with α6 and ß2 or ß3 in recombinant (HEK 293) expression leads to the appearance of a slowly dissociating [3 H]muscimol component. In addition, we compared muscimol currents in recombinant α4ß3δ and α4ß3 receptors and show that δ subunit co-expression leads to highly muscimol-sensitive currents with an estimated EC50 of around 1-2 nM and slow deactivation kinetics. These data indicate that δ subunit incorporation leads to a dramatic increase in GABAA R muscimol sensitivity. We conclude that biochemical and behavioral low-dose muscimol selectivity for δ-subunit-containing receptors is a result of low nanomolar-binding affinity on δ-GABAA Rs.


Assuntos
Encéfalo/metabolismo , Muscimol/metabolismo , Receptores de GABA-A/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica
11.
J Neuroinflammation ; 16(1): 252, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796042

RESUMO

BACKGROUND: Folate receptor-ß (FR-ß) is a cell surface receptor that is significantly upregulated on activated macrophages during inflammation and provides a potential target for folate-based therapeutic and diagnostic agents. FR-ß expression in central nervous system inflammation remains relatively unexplored. Therefore, we used focally induced acute and chronic phases of experimental autoimmune encephalomyelitis (EAE) to study patterns of FR-ß expression and evaluated its potential as an in vivo imaging target. METHODS: Focal EAE was induced in rats using heat-killed Bacillus Calmette-Guérin followed by activation with complete Freund's adjuvant supplemented with Mycobacterium tuberculosis. The rats were assessed with magnetic resonance imaging and positron emission tomography/computed tomography (PET/CT) at acute (14 days) and chronic (90 days) phases of inflammation. The animals were finally sacrificed for ex vivo autoradiography of their brains. PET studies were performed using FR-ß-targeting aluminum [18F]fluoride-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid conjugated folate ([18F]AlF-NOTA-folate, 18F-FOL) and 18 kDa translocator protein (TSPO)-targeting N-acetyl-N-(2-[11C]methoxybenzyl)-2-phenoxy-5-pyridinamine (11C-PBR28). Post-mortem immunohistochemistry was performed using anti-FR-ß, anti-cluster of differentiation 68 (anti-CD68), anti-inducible nitric oxide synthase (anti-iNOS), and anti-mannose receptor C-type 1 (anti-MRC-1) antibodies. The specificity of 18F-FOL binding was verified using in vitro brain sections with folate glucosamine used as a blocking agent. RESULTS: Immunohistochemical evaluation of focal EAE lesions demonstrated anti-FR-ß positive cells at the lesion border in both acute and chronic phases of inflammation. We found that anti-FR-ß correlated with anti-CD68 and anti-MRC-1 immunohistochemistry; for MRC-1, the correlation was most prominent in the chronic phase of inflammation. Both 18F-FOL and 11C-PBR28 radiotracers bound to the EAE lesions. Autoradiography studies verified that this binding took place in areas of anti-FR-ß positivity. A blocking assay using folate glucosamine further verified the tracer's specificity. In the chronic phase of EAE, the lesion-to-background ratio of 18F-FOL was significantly higher than that of 11C-PBR28 (P = 0.016). CONCLUSION: Our EAE results imply that FR-ß may be a useful target for in vivo imaging of multiple sclerosis-related immunopathology. FR-ß-targeted PET imaging with 18F-FOL may facilitate the monitoring of lesion development and complement the information obtained from TSPO imaging by bringing more specificity to the PET imaging armamentarium for neuroinflammation.


Assuntos
Encefalomielite Autoimune Experimental/diagnóstico por imagem , Encefalomielite Autoimune Experimental/metabolismo , Receptor 2 de Folato/metabolismo , Animais , Encefalomielite Autoimune Experimental/induzido quimicamente , Adjuvante de Freund/toxicidade , Masculino , Mycobacterium tuberculosis/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ligação Proteica/fisiologia , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew
12.
Int J Toxicol ; 38(1): 4-11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30663453

RESUMO

The peptide-based radioactive compound [68Ga]Ga-DOTA-Siglec-9 is a novel agent for imaging of inflammation with positron emission tomography. The drug target of [68Ga]Ga-DOTA-Siglec-9 is vascular adhesion protein 1. Previous studies have obtained promising results with [68Ga]Ga-DOTA-Siglec-9 in experimental animals. However, before taking this novel imaging agent into clinical trials, safety and toxicological studies need to be performed with the nonradioactive precursor compound DOTA-Siglec-9. This extended single-dose toxicity study was designed to provide information on the major toxic effects of DOTA-Siglec-9 and to indicate possible target organs after a single intravenous (iv) injection in rats. The study was performed using 60 adult Hsd: Sprague Dawley rats and included a control group and a treatment group to investigate the toxicity of DOTA-Siglec-9 solution at a final concentration of 0.2 mg/mL after a single iv injection of 582 µg/kg. The maximum dose tested was 1,000-fold the clinical dose on a mg/kg basis as indicated in European Medicines Agency International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guideline M3(R2). The planned human clinical dose is approximately 0.582 µg of DOTA-Siglec-9 per kg of body mass. This study demonstrates that iv administration of DOTA-Siglec-9 at a dose of 582 µg/kg was well tolerated in rats and did not produce toxicologically significant adverse effects.


Assuntos
Antígenos CD/toxicidade , Meios de Contraste/toxicidade , Compostos Heterocíclicos com 1 Anel/toxicidade , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/toxicidade , Administração Intravenosa , Animais , Feminino , Masculino , Ratos Sprague-Dawley , Testes de Toxicidade Aguda
13.
J Nucl Cardiol ; 25(4): 1114-1123, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-27914007

RESUMO

BACKGROUND: Matrix metalloproteinases 2 and 9 (MMP-2/9) play a role in extracellular matrix remodeling after an ischemic myocardial injury. We evaluated 68Ga-DOTA-peptide targeting MMP-2/9 for the detection of gelatinase expression after myocardial infarction (MI) in rat. METHODS: Rats were injected with 43 ± 7.7 MBq of 68Ga-DOTA-peptide targeting MMP-2/9 at 7 days (n = 7) or 4 weeks (n = 8) after permanent coronary ligation or sham operation (n = 5 at both time points) followed by positron emission tomography (PET). The left ventricle was cut in frozen sections for autoradiography and immunohistochemistry 30 minutes after tracer injection. RESULTS: Immunohistochemical staining showed MMP-2 and MMP-9 expressing cells, CD31-positive endothelial cells, and CD68-positive macrophages in the infarcted myocardium. Autoradiography showed increased tracer uptake in the infarcted area both at 7 days and 4 weeks after MI (MI-to-remote area ratio 2.5 ± 0.46 and 3.1 ± 1.0, respectively). Tracer uptake in damaged tissue correlated with the amount of CD68-positive macrophages at 7 days after MI, and CD31-positive endothelial cells at 7 days and 4 weeks after MI. The tracer was rapidly metabolized, radioactivity in the blood exceeded that of the myocardium, and tracer accumulation in the heart was not detectable by in vivo PET. CONCLUSIONS: 68Ga-DOTA-peptide targeting MMP-2/9 accumulates in the damaged rat myocardium after an ischemic injury, but tracer instability and slow clearance in vivo make it unsuitable for further evaluation.


Assuntos
Radioisótopos de Gálio , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 9 da Matriz/análise , Infarto do Miocárdio/enzimologia , Animais , Autorradiografia , Masculino , Miocárdio/enzimologia , Tomografia por Emissão de Pósitrons , Ratos , Ratos Sprague-Dawley
14.
Molecules ; 23(2)2018 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-29385091

RESUMO

Amino acid residues 283-297 from sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) form a cyclic peptide ligand targeting vascular adhesion protein-1 (VAP-1). VAP-1 is associated with the transfer of leukocytes from blood to tissues upon inflammation. Therefore, analogs of Siglec-9 peptide are good candidates for visualizing inflammation non-invasively using positron emission tomography (PET). Gallium-68-labeled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA)-conjugated Siglec-9 has been evaluated extensively for this purpose. Here, we explored two alternative strategies for radiolabeling Siglec-9 peptide using a 1,4,7-triazacyclononane-triacetic acid (NOTA)-chelator to bind [68Ga]Ga or [18F]AlF. The radioligands were evaluated by in vivo PET imaging and ex vivo γ-counting of turpentine-induced sterile skin/muscle inflammation in Sprague-Dawley rats. Both tracers showed clear accumulation in the inflamed tissues. The whole-body biodistribution patterns of the tracers were similar.


Assuntos
Antígenos CD , Radioisótopos de Flúor , Isótopos de Gálio , Compostos Heterocíclicos , Marcação por Isótopo/métodos , Tomografia por Emissão de Pósitrons/métodos , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Animais , Antígenos CD/química , Antígenos CD/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos com 1 Anel , Ratos , Ratos Sprague-Dawley , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/química , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/farmacologia
15.
Molecules ; 23(12)2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30513758

RESUMO

Background: The expression of matrix metalloproteinases 2/9 (MMP-2/9) has been implicated in arterial remodeling and inflammation in atherosclerosis. We evaluated a gallium-68 labeled peptide for the detection of MMP-2/9 in atherosclerotic mouse aorta. Methods: We studied sixteen low-density lipoprotein receptor deficient mice (LDLR-/-ApoB100/100) kept on a Western-type diet. Distribution of intravenously-injected MMP-2/9-targeting peptide, [68Ga]Ga-DOTA-TCTP-1, was studied by combined positron emission tomography (PET) and contrast-enhanced computed tomography (CT). At 60 min post-injection, aortas were cut into cryosections for autoradiography analysis of tracer uptake, histology, and immunohistochemistry. Zymography was used to assess MMP-2/9 activation and pre-treatment with MMP-2/9 inhibitor to assess the specificity of tracer uptake. Results: Tracer uptake was not visible by in vivo PET/CT in the atherosclerotic aorta, but ex vivo autoradiography revealed 1.8 ± 0.34 times higher tracer uptake in atherosclerotic plaques than in normal vessel wall (p = 0.0029). Tracer uptake in plaques correlated strongly with the quantity of Mac-3-positive macrophages (R = 0.91, p < 0.001), but weakly with MMP-9 staining (R = 0.40, p = 0.099). Zymography showed MMP-2 activation in the aorta, and pre-treatment with MMP-2/9 inhibitor decreased tracer uptake by 55% (p = 0.0020). Conclusions: The MMP-2/9-targeting [68Ga]Ga-DOTA-TCTP-1 shows specific uptake in inflamed atherosclerotic lesions; however, a low target-to-background ratio precluded in vivo vascular imaging. Our results suggest, that the affinity of gelatinase imaging probes should be steered towards activated MMP-2, to reduce the interference of circulating enzymes on the target visualization in vivo.


Assuntos
Biomarcadores Tumorais , Radioisótopos de Gálio , Compostos Heterocíclicos com 1 Anel , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Animais , Autorradiografia , Biomarcadores Tumorais/química , Modelos Animais de Doenças , Feminino , Radioisótopos de Gálio/química , Compostos Heterocíclicos com 1 Anel/química , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Knockout , Placa Aterosclerótica/patologia , Compostos Radiofarmacêuticos/química , Distribuição Tecidual , Proteína Tumoral 1 Controlada por Tradução
16.
J Nucl Cardiol ; 24(3): 862-871, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27225517

RESUMO

BACKGROUND: Radioligands of 18-kDa translocator protein (TSPO) expressed on activated macrophages are a potential approach for imaging of inflammation in atherosclerosis. We evaluated a novel TSPO-targeted tracer 18F-FEMPA for the detection of atherosclerotic plaque inflammation in mice. METHODS AND RESULTS: The distribution kinetics of 18F-FEMPA was evaluated by in vivo PET/CT imaging. 18F-FEMPA uptake was compared in atherosclerotic (LDLR-/-ApoB100/100, n = 10) and healthy mice (C57BL/6 N, n = 7) ex vivo at twenty minutes post-injection. Biodistribution was analyzed from harvested tissue samples, and aortas were sectioned for autoradiography. Aortas of LDLR-/-ApoB100/100 mice showed large, macrophage-rich atherosclerotic plaques. In vivo, 18F-FEMPA showed rapid blood clearance but no difference in aortic uptake between atherosclerotic and healthy mice. In the mice studied ex vivo at 20 minutes post-injection, quantification of radioactivity in the whole aorta showed 1.3-fold higher 18F-FEMPA accumulation in atherosclerotic than healthy mice (P = .028). Autoradiography showed higher tracer uptake in plaque areas with high macrophage content as compared with areas of no macrophages (count densities 190 ± 54 vs 40 ± 13 PSL/mm2, P < .001), but the uptake in the plaques was not higher than in the normal vessel wall (230 ± 78 PSL/mm2). In vitro blocking showed specific accumulation in mouse and human atherosclerotic plaques. Immunohistochemistry confirmed co-localization of TSPO and macrophages. CONCLUSIONS: 18F-FEMPA shows rapid blood clearance and uptake in the mouse aorta. Uptake in atherosclerotic plaques correlated with the amount of macrophages, but did not exceed that in the normal vessel wall.


Assuntos
Aterosclerose/diagnóstico por imagem , Aterosclerose/metabolismo , Hidrocarbonetos Fluorados/farmacocinética , Piridinas/farmacocinética , Receptores de GABA/metabolismo , Animais , Biomarcadores/metabolismo , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade de Órgãos , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição Tecidual
17.
Nano Lett ; 14(8): 4476-9, 2014 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-24987929

RESUMO

The existence of multiple thermodynamically stable isomer states is one of the most fundamental properties of small clusters. This work shows that the conformational dependence of the Coulomb charging energy of a nanocluster leads to a giant electroresistance, where charging induced conformational distortion changes the blockade voltage. The intricate interplay between charging and conformation change is demonstrated in a nanocluster Zn3O4 by combining a first-principles calculation with a temperature-dependent transport model. The predicted hysteretic Coulomb blockade staircase in the current-voltage curve adds another dimension to the rich phenomena of tunneling electroresistance. The new mechanism provides a better controlled and repeatable platform to study conformational electroresistance.

18.
Acta Oncol ; 53(8): 1125-34, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24957558

RESUMO

UNLABELLED: Somatostatin receptor subtype 2 (sstr2) is regarded as a potential target in malignant gliomas for new therapeutic approaches. Therefore, visualizing and quantifying tumor sstr2 expression in vivo would be highly relevant for the future development of sstr2-targeted therapies. The purpose of this study was to evaluate sstr2 status in experimental BT4C malignant gliomas. METHODS: Rat BT4C malignant glioma cells were injected into BDIX rat brain or subcutaneously into nude mice. Tumor uptake of [(68)Ga]DOTA-(Tyr(3))-Octreotide ([(68)Ga]DOTATOC), a somatostatin analog binding to sstr2, was studied by positron emission tomography/computed tomography (PET/CT). Additionally, subcutaneous tumor-bearing mice underwent PET imaging with 5-deoxy-5-[(18)F]fluororibose-NOC ([(18)F]FDR-NOC), a novel glycosylated peptide tracer also targeting sstr2. Ex vivo tissue radioactivity measurements, autoradiography and immunohistochemistry were performed to study sstr2 expression. RESULTS: Increased tumor uptake of [(68)Ga]DOTATOC was detected at autoradiography with mean tumor-to-brain ratio of 68 ± 30 and tumor-to-muscle ratio of 9.2 ± 3.8 for rat glioma. High tumor-to-muscle ratios were also observed in subcutaneous tumor-bearing mice after injection with [(68)Ga]DOTATOC and [(18)F]FDR-NOC with both autoradiography (6.7 ± 1.5 and 4.3 ± 0.8, respectively) and tissue radioactivity measurements (6.5 ± 0.8 and 4.8 ± 0.6, respectively). Furthermore, sstr2 immunohistochemistry showed positive staining in both tumor models. However, surprisingly low tumor signal compromised PET imaging. Mean SUVmax for rat gliomas was 0.64 ± 0.28 from 30 to 60 min after [(68)Ga]DOTATOC injection. The majority of subcutaneous tumors were not visualized by [(68)Ga]DOTATOC or [(18)F]FDR-NOC PET. CONCLUSIONS: Experimental BT4C gliomas show high expression of sstr2. Weak signal in PET imaging, however, suggests only limited benefit of [(68)Ga]DOTATOC or [(18)F]FDR-NOC PET/CT in this tumor model for in vivo imaging of sstr2 status.


Assuntos
Glioma/metabolismo , Proteínas de Neoplasias/metabolismo , Octreotida/análogos & derivados , Compostos Organometálicos/farmacocinética , Receptores de Somatostatina/metabolismo , Animais , Autorradiografia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Linhagem Celular Tumoral , Fluordesoxiglucose F18/farmacocinética , Glioma/diagnóstico por imagem , Masculino , Camundongos , Camundongos Nus , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/metabolismo , Transplante de Neoplasias/métodos , Octreotida/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Tomografia Computadorizada por Raios X/métodos
19.
Zhong Yao Cai ; 37(9): 1525-8, 2014 Sep.
Artigo em Zh | MEDLINE | ID: mdl-25857148

RESUMO

OBJECTIVE: Less fungicides could be used to biocontrol Alternaria panax and Botrytis cinerea, this experiment can offer preliminary theory for wood vinegar as a botanic fungicide. METHODS: The in vitro inhibition activities of wood vinegar on Alternaria panax and Botrytis cinerea were tested by using mycelial growth rate method and spore germination method. RESULTS: Inhibition of mycelium growth rate to Alternaria panax was 100% when the concentration of wood vinegar was no less than 3.0%, while the inhibition of mycelium growth rate and spore germination rate were 70.68% and 84.47%, respectively, at concentration of wood vinegar 2.25%. Inhibition of mycelium growth rate and spore germination rate to Botrytis cinerea were 100% when the concentration of wood vinegar was no less than 2.25%. CONCLUSION: Wood vinegar concentration of no less than 2.25% can be used as a biocontrol agent of Alternaria panax and Botrytis cinerea, it is useful for the further field trial.


Assuntos
Alternaria , Botrytis , Ácido Acético , Antifúngicos , Metanol , Micélio
20.
Sleep Med Rev ; 77: 101967, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38936220

RESUMO

The quality of sleep plays a significant role in determining human well-being, and studying sleep and sleep disorders using various methods can aid in the prevention and treatment of diseases. Positron emission tomography (PET) is a noninvasive and highly sensitive medical imaging technique that has been widely adopted in the clinic. This review article provides data on research activity related to sleep and sleep apnea and discusses the use of PET in investigating sleep apnea and other sleep disorders. We conducted a statistical analysis of the number of original research articles published on sleep and sleep apnea between 1965 and 2021 and found that there has been a dramatic increase in publications since 1990. The distribution of contributing countries and regions has also undergone significant changes. Although there is an extensive body of literature on sleep research (256,399 original research articles during 1965-2021), PET has only been used in 54 of these published studies, indicating a largely untapped area of research. Nonetheless, PET is a useful tool for identifying connections between sleep disorders and pathological changes in various diseases, including neurological, metabolic, and cardiovascular disorders, as well as cancer. To facilitate the broader use of PET in sleep apnea research, further studies are needed in both clinical and preclinical settings.


Assuntos
Tomografia por Emissão de Pósitrons , Síndromes da Apneia do Sono , Humanos , Tomografia por Emissão de Pósitrons/métodos , Síndromes da Apneia do Sono/diagnóstico por imagem , Pesquisa Biomédica
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